The clinical pharmacology of antineoplastic agents used in the treatment of pediatric malignancies is studied. Emphasis is placed on the role of clinical pharmacologic monitoring and on both pre-clinical and clinical pharmacologic studies of Phase I agents. The clinical pharmacology of orally administered antileukemic agents has been evaluated and the limited bioavailability and variable drug levels of 6-MP achieved following oral administration has been documented. Studies are underway to determine the extent to which this phenomenon is the cause of treatment failure. The interaction of 6-MP and allopurinol, a unique example of hepatic first-pass metabolism in cancer chemotherapy has been examined in both subhuman primates and in man. Additional efforts to optimize 6-MP administration have been based on in vitro studies which have demonstrated a need for prolonged exposure to cytocidal concentrations of drug to maximize leukemic cell kill. A clinical protocol evaluating prolonged intravenous 6-MP infusions in a Phase I setting is underway. Pre-clinical and clinical pharmacokinetic studies of the new agent, Tiazofurin, have been pursued and a pediatric Phase I study of this agent is in progress. A major effort of this project is to study experimental approaches to the treatment of both meningeal and non-meningeal CNS malignancy. A unique subhuman primate model which allows sterile, repetitive access to cerebrospinal fluid, is utilized to study the CNS pharmacokinetics of various intrathecally and intravenously administered chemotherapeutic agents; to evaluate the neurotoxicities attendant upon various CNS treatments; and to evaluate and screen in a pre-clinical setting newer CNS treatment modalities and drug schedules. Information gained from the studies with this model is then applied to the design of clinical treatment protocols. A clinical study of intrathecal AZQ is in progress. Pre-clinical studies evaluating intra-CSF drug administration via indwelling drug delivery devices is under way.